CN103360329B - One class compound phenazine and preparing the application in antitumor drug - Google Patents
One class compound phenazine and preparing the application in antitumor drug Download PDFInfo
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- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 26
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 26
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 title abstract description 12
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 title abstract description 3
- 229940125904 compound 1 Drugs 0.000 claims abstract description 32
- 229940125782 compound 2 Drugs 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 15
- 201000007270 liver cancer Diseases 0.000 claims description 11
- 208000014018 liver neoplasm Diseases 0.000 claims description 11
- 230000001348 anti-glioma Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims 3
- 206010018338 Glioma Diseases 0.000 claims 3
- 206010023774 Large cell lung cancer Diseases 0.000 claims 2
- -1 Phenazine compound Chemical class 0.000 claims 2
- 201000009546 lung large cell carcinoma Diseases 0.000 claims 2
- 150000002988 phenazines Chemical class 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 14
- 239000000284 extract Substances 0.000 description 10
- 238000011218 seed culture Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 241001446247 uncultured actinomycete Species 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012531 culture fluid Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000012916 structural analysis Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a class compound phenazine and preparing the application in antitumor drug.Azophenlyene compounds-compound 1 of the present invention and compound 2 are new compounds, its structural formula is as shown in formula I, this azophenlyene compounds-compound 1 and compound 2 pairs of tumour cells inhibited, may be used for preparing antitumor drug, be used for the treatment of tumour, therefore the present invention is that the new antitumor drug of exploitation provides compound candidate, has great importance to exploitation Chinese Sea drug resource.
in formula I, compound 1:R=H; Or compound 2:R=Me.
Description
Technical field:
The invention belongs to natural product field, be specifically related to two azophenlyene compounds and preparing the application in antitumor drug.
Background technology:
For a long time, malignant tumour has become one of principal disease of serious harm human life and quality of life.It is reported, malignant tumour has become the primary cause of the death of China resident, and along with ineffective to environment protection of expanding economy and people, the lethality rate of malignant tumour is also in continuous growth.The World Health Organization predicts, to the year two thousand twenty, will have 2,000 ten thousand de novo malignancy cases, wherein death toll reaches 1,200 ten thousand, and the overwhelming majority will occur in developing country.For the treatment of malignant tumour, natural product and derivative medicine thereof play an important role.It is reported, between 1981 to 2008, the antitumor drug in natural product source accounts for more than 60% of listing antitumor drug, and, new type natural product and derivative thereof as quantity shared by new antitumor drug also in continuous increase.
Summary of the invention:
First object of the present invention is to provide azophenlyene compounds or its pharmaceutical salts that two have anti-tumor activity.
Azophenlyene compounds of the present invention or its pharmaceutical salts, its structural formula is as shown in formula I:
In formula I, compound 1:R=H; Or compound 2:R=Me.
The present inventor is by the HPLC-DAD atlas analysis to marine actinomycete StreptomycesniveusSCSIO3406 fermented product extract, find that it produces secondary metabolite characteristic ultraviolet absorption distinct and more rare, amplify fermentation and extraction purification by shaking table, from 3406, obtain compound 1 and compound 2 respectively.Through structural analysis, it is confirmed as azophenlyene compounds, concrete structure as shown in formula I, wherein compound 1:R=H; Compound 2:R=Me.By the antitumor activity evaluation to compound 1 and compound 2, find compound 1 and compound 2 pairs of neuroglial cytoma strains (SF-268), breast carcinoma cell strain (MCF-7), National People's Congress's sclc cell line (NCI-H460) and human liver cancer cell (HepG-2) inhibited, the especially IC of compound 1 couple of tumor cell line SF-268 and MCF-7
50equal <20 μM, can as the lead compound of antitumor drug exploitation.
Therefore second object of the present invention is to provide compound 1 as shown in formula I or compound 2, or its pharmaceutical salts is preparing the application in antitumor drug.
When for compound 1, described antitumor drug is preferably the medicine of anti-glioma, mammary cancer, National People's Congress's cell lung cancer or people's liver cancer, more preferably the medicine of anti-glioma or mammary cancer.
When for compound 2, described antitumor drug is preferably the medicine of anti-glioma, mammary cancer or people's liver cancer, more preferably the medicine of anti-glioma or mammary cancer.
3rd object of the present invention is to provide a kind of antitumor drug, it is characterized in that, includes the compound 1 as shown in formula I as active ingredient or the compound 2 of effective amount, or its pharmaceutical salts, and pharmaceutically acceptable carrier.
When for compound 1, described antitumor drug is preferably the medicine of anti-glioma, mammary cancer, National People's Congress's cell lung cancer or people's liver cancer, more preferably the medicine of anti-glioma or mammary cancer.
When for compound 2, described antitumor drug is preferably the medicine of anti-glioma, mammary cancer or people's liver cancer, more preferably the medicine of anti-glioma or mammary cancer.
Azophenlyene compounds-compound 1 of the present invention and compound 2 are new compounds, inhibited to tumour cell, may be used for preparing antitumor drug, be used for the treatment of tumour, therefore the present invention is that the new antitumor drug of exploitation provides compound candidate, has great importance to exploitation Chinese Sea drug resource.
Marine actinomycete StreptomycesniveusSCSIO3406 of the present invention is preserved in China General Microbiological culture presevation administrative center (CGMCC) on July 2nd, 2013, address: Yard 1, BeiChen xi Road, Chaoyang District, Beijing City institute of microbiology of the Chinese Academy of Sciences, its deposit number is: CGMCCNO.7863.
Accompanying drawing illustrates:
Fig. 1 is 1H-1HCOSY and part HMBC, the NOESY relevant information of compound 1-2, wherein 1 representation compound 1,2 representation compound 2.
Embodiment:
Following examples further illustrate of the present invention, instead of limitation of the present invention.
Embodiment 1:
Compound 1 as shown in formula I or the preparation of compound 2 and Structural Identification
One, the compound 1 as shown in formula I or the preparation of compound 2
1. seed culture:
(1) seed culture based formulas: by massfraction 100%, comprises Zulkovsky starch 0.5%, soyflour 0.5%, yeast extract paste 0.2%, peptone 0.2%, K
2hPO
40.05%, MgSO
47H
2o0.05%, NaCl0.4%, thick sea salt 0.3%, pH7.2-7.4, CaCO
30.2%, surplus is water.Mixed by above-mentioned substance according to formula, be sub-packed in the Erlenmeyer flask of 250mL, every bottled 50mL after preparing, 121 DEG C of sterilizings 20 minutes, as seed culture medium for subsequent use.
(2) cultivation of seed: the mycelium of marine actinomycete StreptomycesniveusSCSIO3406 or spore are linked in above-mentioned seed culture medium, with the rotating speed of 200rpm, at 28 DEG C, shaking table is cultivated 36 hours must seed culture fluid.
2. amplify fermentation culture:
(1) fermentative medium formula is amplified: by massfraction 100%, comprise Zulkovsky starch 0.5%, soyflour 0.5%, yeast extract paste 0.2%, peptone 0.2%, K
2hPO
40.05%, MgSO
47H
2o0.05%, NaCl0.4%, thick sea salt 0.3%, pH7.2-7.4, CaCO
30.2%, surplus is water.Mixed by above-mentioned substance according to formula, amount to 24L in batches after preparing and amplify fermention medium, be sub-packed in the Erlenmeyer flask of 1000mL, every bottled 200mL after preparing, 121 DEG C of sterilizings 20 minutes, as amplification fermention medium for subsequent use.
(2) fermentation culture:
Under aseptic technique, be inoculated in respectively by cultured seed culture fluid and amplify in fermention medium, every 1000ml Erlenmeyer flask (amplifying fermention medium containing 200mL) inoculates one bottle of seed culture fluid (50mL).The access of 50ml seed culture fluid is equipped with 200mL and is amplified in the 1000mL Erlenmeyer flask of fermention medium, and with the rotating speed of 200rpm, at 28 DEG C, shaking table cultivates 7 days to obtain the fermenting culture of marine actinomycete StreptomycesniveusSCSIO3406.
3. extraction and isolation:
By the fermenting culture of above-mentioned marine actinomycete StreptomycesniveusSCSIO3406, centrifugal with 3600rpm, obtain supernatant fermented liquid and precipitation mycelium.Supernatant fermented liquid butanone equal-volume extracts 3 times, and butanone extraction liquid is obtaining fermented liquid medicinal extract lower than 40 DEG C of concentrating under reduced pressure; Precipitation mycelium extracts three times repeatedly with altogether 3L acetone, and acetone extract liquid concentrating under reduced pressure at lower than 40 DEG C obtains thalline medicinal extract; After HPLC-DAD detects, merging fermented liquid medicinal extract and thalline medicinal extract amount to obtain about 25.3g medicinal extract.This medicinal extract 100-200 order silica gel is separated, and after mixing sample, dry column-packing, adopts chloroform/methanol (100/0,98/2,95/5,92/8,90/10,80/20,50/50, v/v) gradient elution order to obtain 7 components (A1-A7).The cut of component A1(chloroform/methanol 100/0 wash-out) use petrol ether/ethyl acetate (P/E, v/v) with 100%(volume fraction) sherwood oil is initial, with 4%(volume fraction) gradient increase polarity, further separation, obtain B component 3-B5 (P/E respectively, 92/8-84/16, and B6-B8 (P/E v/v), 80/20-72/28, v/v), merge B component 3-B5, under the flow velocity of 2.5ml/min, take 274nm as determined wavelength, with 90% acetonitrile (acetonitrile/water, v/v) constant gradient partly prepares high-pressure liquid phase separation (SP-HPLC) (Hitachi (HITACHI), UV-detector is L-2455, pump is L-2130, pillar model: reversed-phase column is YMC-PackODS-Acolumn (250 × 10mm, 5 μm)), in 23.7min retention time, place obtains compound 1(20.5mg).Merge B component 6-B8, be prepared into compound 2(12.4mg with the elution requirement SP-HPLC identical with component B3-B5), its retention time is 22.8.
Two, the Structural Identification of compound 1 and compound 2
Structural analysis test is carried out to compound 1 and compound 2, obtains following physico-chemical property data:
Compound 1: yellow powder; UV (CHCl
3) λ
max(log ε) 274 (4.76), 233 (4.06) nm; IR (ATR) ν
max3566,2965,2926,2864,1533,1485,802,737cm
-1;
1h and
13cNMR data are in table 1; (+)-HRESIMSm/z349.1918 [M+H]
+(calcdforC
22h
25n
2o
2, 349.1911), (+)-HRESIMSm/z371.1728 [M+Na]
+(calcdforC
22h
24n
2naO
2, 371.1730).
Compound 2: yellow powder; UV (CHCl
3) λ
max(log ε) 274 (4.74), 233 (4.11) nm; IR (ATR) ν
max2955,2922,2851,1487,1150,804,739cm
-1;
1h and
13cNMR data are in table 1; (+)-HRESIMSm/z363.2074 [M+H]
+(calcdforC
23h
27n
2o
2, 363.2067), (+)-HRESIMSm/z385.1887 [M+Na]
+(calcdforC
23h
26n
2naO
2, 385.1886).
Table 1 compound 1 and 2 is at CDCl
3in
1h (500MHz) and
13cNMR (125HMz) data
The 2DNMR relevant information of compound 1 and compound 2 is as Fig. 1:
Analyze known according to above physicochemical data, the concrete structure of compound 1 and compound 2 is as formula I.
In formula I, compound 1:R=H; Or compound 2:R=Me.
Embodiment 2:
To the experiment of the azophenlyene compounds-compound 1 of embodiment 1 and the antitumor cell of compound 2
Adopt international tumor cell line, that is: neuroglial cytoma strain (SF-268), breast carcinoma cell strain (MCF-7), National People's Congress's sclc cell line (NCI-H460), and human liver cancer cell (HepG-2).Test method is international srb assay:
1) cell cultures.According to vitro growth rates, tumour cell (the neuroglial cytoma strain (SF-268) of logarithmic phase will be in, breast carcinoma cell strain (MCF-7), National People's Congress's sclc cell line (NCI-H460) or human liver cancer cell (HepG-2)) be inoculated in 96 orifice plates with 180 μ L/ holes, adherent growth 24 hours.
2) sample (medicine) is added.Every hole adds the compound 1 of 20 μ L different concns or the normal saline solution of compound 2.And establish the physiological saline Vehicle controls of respective concentration and acellular withered hole.
3) dosing cell cultures.Tumour cell is at 37 DEG C, the CO of 5%
2cultivate 72 hours under condition.
4) active testing.Cell after cultivating, incline nutrient solution, and every hole adds the 50% cold TCA solid cell of 50 μ L, and then adopt the SRB of 0.4% to dye 30 minutes, the acetic acid with 1% washs 5 times, dry air.Finally add the Tris solution in 200 μ L/ holes, microplate reader 570nm wavelength measures OD value.Using cis-platinum as positive control.
5) active reporter.Every strain clone does three parallel laboratory tests, and experimental result is in table 2:
Table 2: the restraining effect (IC of compound 1 and 2 pairs of tumor cell lines
50, μM)
apositive control
Above-mentioned experimental result shows, compound 1 and compound 2 pairs of tumour cells have certain restraining effect, the especially IC of compound 1 couple of tumor cell line SF-268 and MCF-7
50all below 20 μMs, show medium inhibiting tumour cells active.Therefore the present invention can be the new antitumor drug of development and provides new lead compound, significant to the exploitation of Chinese marine pharmaceutical resource.
To sum up, the present invention is that the new antitumor drug of development provides new lead compound, has great importance to exploitation Chinese Sea drug resource.
Claims (3)
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| CN105112322B (en) * | 2015-08-07 | 2018-07-06 | 浙江大学 | Grey mold quinone A and B and preparation method thereof and medical usage |
| CN106554321B (en) * | 2015-09-25 | 2019-05-28 | 陆源 | A kind of azophenlyene substance, preparation method and its application |
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